Method of controlling body temperature while reducing shivering

ABSTRACT

A method and apparatus for lowering the body temperature of a patient while reducing shivering by using a heat exchange device in combination with an α 2 -adrenoreceptor agonist, a non-opiod analgesic monoamine uptake inhibitor or neuropeptide that temporarily reduces shivering. The devices disclosed include a catheter having a heat exchange balloon thereon with heat exchange fluid circulating through the interior of the balloon. The heat exchange balloon is placed in the vasculature of a patient, and heat exchange fluid at a temperature other than the temperature of the blood in the vasculature is circulated through the interior of the balloon to add or remove heat from the blood of the patient. Various α 2 -adrenoreceptor agonistα 2 -adrenoreceptor agonists, non-opiod analgesic monoamine uptake inhibitors and neuropeptides are disclosed including dexmedetomidine, nefopam, neurotensin and anticonvulsant medications and pharmaceutically acceptable salts thereof. A control system for the control of the patient&#39;s temperature is disclosed for controlling the patient&#39;s temperature in conjunction with administering the α 2 -adrenoreceptor agonist, non-opiod analgesic monoamine uptake inhibitor or neuropeptide.

RELATED PATENT APPLICATION

[0001] This invention is related to the invention disclosed in thecopending, coassigned patent application of Dae, et al., for Method ofControlling Body Temperature While Reducing Shivering, U.S. Ser. No.09/372,714, filed on Aug. 11, 1999.

INTRODUCTION TECHNICAL FIELD

[0002] This invention relates to a method, apparatus and composition forselectively controlling the temperature of all or a portion of apatient's body by lowering, maintaining or raising the temperature of abody fluid or tissue to affect the temperature of all or part of thepatient's body, while reducing shivering that typically accompanies suchtemperature control. More particularly, the invention relates to a heatexchange device in combination with an anti-shivering mechanism tocontrol the temperature of all of a portion of a patient's body whilereducing shivering. The invention also relates to novel compositionsthat are useful for reducing shivering.

BACKGROUND

[0003] The “set point temperature” is the temperature that the bodyattempts to maintain through the thermoregulatory responses. Underordinary circumstances, thermoregulatory mechanisms within the humanbody which include sweating and vasodilation to enhance heat loss,arterio venous (“AV”) shunting and vasoconstriction to enhance retainingheat, and shivering to enhance increased generation of body heat, serveto maintain the body at a near constant set point temperature of about37° C. (98.6° F.), often referred to as “normothermic”. However,sometimes the body sets a different set point temperature, for example apatient with a fever has an elevated set point temperature, and thesemechanisms can serve to maintain an elevated temperature. In the case ofa fever, the set point temperature can be higher than normothermic.

[0004] There is a temperature slightly below the set point temperaturewhere the body senses that the body temperature is too low and begins toshiver. This temperature is sometimes referred to as the shiveringthreshold. As with the set point temperature, the shivering threshold isnot an absolute temperature but varies between individuals and withinthe same individual depending on his or her condition.

[0005] As a result of the thermoregulatory mechanisms, any heat lost tothe environment is precisely balanced by heat produced within the body.Accordingly, attempts to control the body temperature below the setpoint temperature often produce shivering in the patient, as this is themain method of generating additional metabolic heat. Shivering canincrease heat production by 200-500% and thus presents a seriousobstacle when attempts are made to reduce a patient's body temperature.

[0006] The thermoregulatory mechanisms provide a formidable defense whenattempts are made to lower the body temperature below the set pointtemperature, for example, when one attempts to induce an artificiallylow body temperature (a condition known as hypothermia) by lowering thenormothermic 37° C. to a lower temperature state or when one attempts tomaintain normothermia by lowering an elevated body temperature tonormothermic 37° C. Since there are numerous therapeutic reasons forboth inducing hypothermia or inducing normothermia in a patientsuffering from an elevated temperature, the thermoregulatory mechanismsmust be taken into consideration when designing a therapeutic regimenfor controlling the temperature of all or a portion of a patient's body.Indeed, when the patient has a set point temperature that is abovenormothermic, for example when the patient has a fever, the shiveringthreshold may actually be above normothermic as well, and thus even anattempt to maintain a patient's temperature to normothermia may resultin shivering. In addition, even when the thermoregulatory mechanismshave been overcome, the body temperature may continue to drop, possiblybelow the desired threshold. This “overshooting” phenomenon can lead tocomplications. Accordingly, any therapeutic regimen for controlling bodytemperature preferably does so at a carefully monitored and controlledrate.

[0007] It has also been found that in rewarming a patient, either aftertherapeutic hypothermia or a patient suffering from accidentalhypothermia, a very gradual and controlled rewarming rate is desirable.The dramatic generation of metabolic heat due to shivering, particularlyin addition to heat added by other means, can result in rapid anduncontrolled rewarming. Therefore therapeutic rewarming at a carefullymonitored and controlled rate also requires control over shivering.

[0008] Hypothermia may be induced to minimize damage to the brain when apatient has suffered a head injury or stroke, or to minimize damage toheart and brain tissue when a patient has undergone cardiac arrest. Itmay sometimes also be desirable to induce hypothermia during surgery,especially neurosurgery, once again to minimize tissue damage.

[0009] Early techniques involved application of cold to the skin surfaceor cooling the inspired air, alone or in combination with a compound toinhibit the thermoregulatory center such as chlorpromazine (Ripstein, etal., Surgery (35)1:98-103 (1954)). More recently, in situ bloodtemperature modification using a heat exchange catheter was described inGinsburg, U.S. Pat. No. 5,486,208 and Ginsburg, WP 98/268831, thedisclosures of which are incorporated herein by reference. This in situprocedure lowers the body temperature much faster and maintains thetemperature at that lower level more precisely than the cooled skinsurface or cooled breathing air methods described above.

[0010] There are also drugs which are capable of assisting in loweringbody temperature. However, many require toxic doses in order to achievethe desired hypothermic state. Temperature lowering was also allegedlyachieved with chlorpromazine, when administered in combination with arefrigeration blanket (Ripstein, et al, supra), and when administeredalone (Chai, et al., Br. J. Pharmac. 57:43-49 (1976)). However, in boththese instances, temperature variation after the chlorpromazine wasadministered was achieved by external cooling or exposure alone andwithout any significant control of the degree or rate of body cooling.More recently, hypothermia was allegedly induced in rats with acombination of a κ opioid receptor agonist and a dopamine receptorblocker or agonist (Adler, et al., U.S. Pat. No. 4,758,562). It has beenshown that the α₂-adrenoreceptor agonists dexmedetomidine and clonidineare able to lower the shivering threshold (Talke, et al., Anesthesiology87(4):835-841, 1997). In this study, patients at a normal temperaturewere warmed until sweating then cooled until shivering occurred, as theα₂-adrenoreceptor agonist was administered. Evaluation of the ability ofthese agonists and a novel agonist to reduce core temperature were laterdescribed in Millan, et al., The Journal of Pharmacology andExperimental Therapeutics 295(3):1192-1205, 2000. However, in both thesestudies, as with chlorpromazine, temperature variation after theα₂-adrenoreceptor agonist was administered was achieved with only minorcontrol of the degree or rate of body cooling.

[0011] However, in spite of these advances, there continues to be a needto develop a method of safely and temporarily inactivating the shiveringresponse while inducing hypothermia or otherwise reducing the body'stemperature below its set point temperature for an extended period oftime, or while gently and slowly raising the body's temperature from ahypothermic state.

SUMMARY

[0012] The present invention pertains to a method for controlling thetemperature of all or a portion of a patient's body to a temperaturebelow its set point temperature, while reducing shivering, comprisingthe steps of: (a) sensing the temperature of all or a portion of thepatient's body; (b) generating a signal based upon the sensedtemperature; (c) controlling the temperature of all or a portion of thepatient's body based upon the signal; and (d) administering an agentselected from the group consisting of α2-adrenoreceptor agonists,non-opiod analgesic monoamine uptake inhibitors ,neuropeptides, nefopamand an anticonvulsant drug to the patient.

[0013] In many ways, the muscular activity of shivering, which is a highfrequency, random-like muscular contraction that is not coordinated toproduce intentional motion, is similar to the high frequency,random-like muscular activity exhibited during some seizures,particularly tonic-clonic seizures. The anticonvulsant medications thatact to inhibit the seizures also may act to inhibit the shivering of apatient which is cooled below the shivering threshold. There may also bea more generalized pharmacological inhibition of the thermoregulatoryresponse of the patient which is helpful when the patient's temperatureis controlled by an endovascular cooling system as described below andnot by the natural thermoregulatory mechanisms of the body.

[0014] The anticonvulsant drugs includes any of the pharmaceuticallyacceptable anticonvulsant medications including without limitationcurrently known anticonvulsant drugs which may be useable in accordancewith this invention include but are not limited to hydantoins (e.g.,phenytoin (Dilantin)), anticonvulsant barbiturates (e.g.,phenobarbital), deoxybarbiturates (e.g., primidone), iminostilbenes(e.g., carbamazepine (Tegretol)), succinimides (e.g., ethosuximide,methsuximide, phensuximide), oxazolidinediones (e.g., trimethadione,paramethadione), benzodiazepines (e.g., diazepam, chlordiazeppoxide,oxazepam, chlorazepate, nitrazepam, clonazepam, lorazepam), acetylureas(e.g., phenacemide, pheneturide) and sulfonamides and carbonic anhydraseinhibitors (e.g., acetazolamide, sulthiame, bromide). ,), gabapetin,lamotrigine, primidone, and valproate or pro-drugs or metabolicprecursors of any such anticonvulsant agents. Because of its method ofadministration, dosage and availability, phenytoin is described indetail below. That does not preclude the use of the other drugs in thisinvention. Furthermore, it is also known that the effectiveness of theanti-shivering drugs may be greatly enhanced by the application of awarming blanket at the times when the patient is at or below what wouldbe the patient's shivering threshold if the drugs had not beenadministered. Thus any of the methods described below may include thestep of placing a warming blanket over the surface of the patient at thesame time as administering the anti-shivering drugs.

[0015] In one embodiment of the invention, the aforementioned method isutilized to lower a patient's body temperature below its set pointtemperature while reducing shivering.

[0016] In yet another embodiment of the invention, the aforementionedmethod is utilized to raise a patient's body temperature from an initialtemperature below the set point temperature while reducing shivering.

[0017] Another embodiment of this invention is to utilize theaforementioned method to raise a patient's body temperature at apredetermined rate while reducing shivering.

[0018] Still another embodiment of the invention is to utilize theaforementioned method to slowly and controllably rewarm a hypothermicpatient from a temperature below the set point temperature towardnormothermia.

[0019] Another embodiment of the invention is to utilize theaforementioned method to maintain a patient's body temperature at astable temperature below the set point temperature while reducingshivering.

[0020] Yet another embodiment of the invention comprises controlling apatient's body temperature by placing a heat exchange device having aheat exchange region into the vascular system of the patient andcontrolling the temperature of the heat exchange region for a sufficienttime to affect the temperature of all or a portion of the patient'sbody, while administering an agent selected from the group consisting ofα2-adrenoreceptor agonists, non-opiod analgesic monoamine uptakeinhibitors, neuropeptides, nefopam and an anticonvulsant drug to thepatient.

[0021] Still another embodiment of the invention is a method ofcontrolling a patient's body temperature by administering an agentselected from the group consisting of α2-adrenoreceptor agonists,non-opiod analgesic monoamine uptake inhibitors, neuropeptides, nefopamand an anticonvulsant drug to the patient while using a heat exchangedevice that is a catheter and the heat exchange region comprises aballoon on the catheter, the temperature of the balloon being controlledby the circulation of a heat exchange fluid through the interior of theballoon. The catheter may have a shaft for the circulation of heatexchange fluid, where fluid circulates through the shaft and through theinterior of the balloon.

[0022] Another embodiment of the invention relates to controlling thetemperature of all or a portion of a patient's body by using a heatexchange device in combination with an agent selected from the groupconsisting of α2-adrenoreceptor agonists, non-opiod analgesic monoamineuptake inhibitors, neuropeptides, nefopam and an anticonvulsant drug orpharmaceutically acceptable salt thereof.

[0023] Yet another embodiment of the invention is a method ofcontrolling the temperature of a patient by using a heat exchange deviceand administering dexmedetomidine.

[0024] Yet another embodiment of the invention is a method ofcontrolling the temperature of a patient by using a heat exchange deviceand administering nefopam.

[0025] Yet another embodiment of the invention is a method ofcontrolling the temperature of a patient by using a heat exchange deviceand administering neurotensin.

[0026] In yet anther embodiment of the invention, a method is providedfor controlling the temperature of a patient by using a heat exchangedevice and administering an anticonvulsant drug.

[0027] In yet anther embodiment of the invention, a method is providedfor controlling the temperature of a patient by using a heat exchangedevice and administering an intravenous dose of fosphenytoin.

[0028] The present invention further comprises a method of controlling apatient's body temperature below its set point temperature with aninternal heat exchange device, while simultaneously inactivating theshivering response of the patient.

[0029] One embodiment of the invention pertains to a method ofcontrolling the temperature of a patient below the set point temperaturecomprising the steps of: (a) employing internal in vivo core temperatureregulation; and (b) administering an α2-adrenoreceptor agonist.

[0030] One embodiment of the invention pertains to a method ofcontrolling the temperature of a patient below the set point temperaturecomprising the steps of: (a) employing internal in vivo core temperatureregulation; and (b) administering of an anticonvulsant drug.

[0031] One embodiment of the invention pertains to a method ofcontrolling the temperature of a patient below the set point temperaturecomprising the steps of: (a) employing internal in vivo core temperatureregulation; (b) placing a warming blanket over the surface of thepatient, and (c) administering an anticonvulsant drug.

[0032] In another embodiment of the invention, the step of employinginternal in vivo core temperature regulation comprises placing a heatexchange device in the blood vessels of the patient, where the heatexchange device has a heat exchange region which is in contact with theflowing blood of the patient; and controlling the temperature of theheat exchange region for a sufficient time to affect the temperature ofthe patient, while administering an agent selected from the groupconsisting of α2-adrenoreceptor agonists, non-opiod analgesic monoamineuptake inhibitors, neuropeptides, nefopam and an anticonvulsant drug tothe patient.

[0033] Yet another embodiment of the invention is a kit for reducing thetemperature of a patient comprising a heat exchange device and an agentselected from the group consisting of α2-adrenoreceptor agonists,non-opiod analgesic monoamine uptake inhibitors and neuropeptides. Thekit may further comprising a set of instructions for use of the heatexchange device and/or administration of the agent. The kit may alsocomprise a control system which measures patient body temperature andcontrols the heat exchange device in response to the body temperature.

[0034] These and other embodiments of the invention are achieved by themethod, apparatus, kit and composition described herein where apatient's body temperature is lowered, such as by inducing hypothermia,utilizing a heat exchange device in combination with an agent selectedfrom the group consisting of α2-adrenoreceptor agonists, non-opiodanalgesic monoamine uptake inhibitors, neuropeptides, nefopam and ananticonvulsant drug. . Such device can comprise an elongate flexiblecatheter having a heat exchanger that operates to exchange heat betweentissue, blood or other body fluid that flows in or is positioned in heatexchanging proximity thereto.

[0035] Further aspects and details of the present invention will becomeapparent to those of skill in the relevant art upon reading andunderstanding of the detailed description of preferred embodiments setforth here below. Each of the embodiments disclosed below may beconsidered individually or in combination with any of the othervariations and aspects of the invention.

BRIEF DESCRIPTION OF THE DRAWING

[0036]FIG. 1 depicts a heat exchange device inserted percutaneously intoa blood vessel of a patient.

[0037]FIG. 2 illustrates a heat exchange device having a heat exchangeregion positioned within the left common carotid artery.

[0038]FIG. 3 depicts a heat exchange catheter having a heat exchangeballoon and a plurality of heat transfer fins.

[0039]FIG. 4 is a cross-sectional view of the distal end of the cathetertaken along line 4-4 of FIG. 3.

[0040]FIG. 5 is a cross-sectional view of the central section of thecatheter taken along line 5-5 of FIG. 3.

[0041]FIG. 6 is a cross-sectional view of the proximal end of thecatheter taken along line 6-6 of FIG. 3.

[0042]FIG. 7 illustrates an alternative construction of a heat exchangecatheter.

[0043]FIG. 8 is a cross-sectional view of the distal end of the cathetertaken along line 8-8 of FIG. 7.

[0044]FIG. 9 is a cross-sectional view of a portion of the centralsection of the catheter taken along line 9-9 of FIG. 7.

[0045]FIG. 10 is a cross-sectional view of another portion of thecentral section of the catheter taken along line 10-10 of FIG. 7.

[0046]FIG. 11 is a cross-sectional view of the proximal end of thecatheter taken along line 11-11 of FIG. 7.

[0047]FIG. 12 is a cross-sectional view of the proximal shaft of thecatheter taken along line 12-12 of FIG. 7.

[0048]FIG. 13 depicts another embodiment a heat exchange catheter, asassembled.

[0049]FIG. 14 shows the shaft member of the catheter assembly of FIG.13.

[0050]FIG. 15 illustrates the balloon configuration of the catheterassembly of FIG. 13.

[0051]FIG. 16 is a cross-sectional view of the balloon of FIG. 15 takenalong line 16-16.

[0052]FIG. 17 is a cross-sectional view of the shaft of FIG. 13 takenalong line 17-17.

[0053]FIG. 18 is a cross-sectional view of the catheter of FIG. 13 takenalong line 18-18.

[0054]FIG. 19 is a view of a portion of the catheter of FIG. 13illustrating outflow of heat exchange fluid.

[0055]FIG. 20 is a cross-sectional view of the catheter of FIG. 13 takenalong line 20-20.

[0056]FIG. 21 is a view of a portion of the catheter of FIG. 13illustrating inflow of heat exchange fluid.

[0057]FIG. 22 is a cross-sectional view of the catheter of FIG. 13 takenalong line 22-22.

[0058]FIG. 23 is a flow chart illustrating a preferred method of theinvention.

[0059]FIG. 24 is a front view of control system useful in the methods ofthe invention.

[0060]FIG. 25 illustrates a control system in operation.

DETAILED DESCRIPTION

[0061] The present invention comprises a method of controlling apatient's body temperature to a temperature below its set pointtemperature, such as inducing hypothermia, while simultaneouslycombating thermoregulatory responses of the patient. More specifically,the invention provides for a method, apparatus, kit and composition forreducing the body's temperature below its set point temperature for anextended period of time while temporarily inactivating the shiveringresponse.

[0062] Inactivation of the thermoregulatory mechanisms allows one tolower the body temperature below the set point temperature whilereducing shivering in the patient. The methods described hereininactivate the thermoregulatory response by means of an agent selectedfrom the group consisting of α2-adrenoreceptor agonists, non-opiodanalgesic monoamine uptake inhibitors, neuropeptides, nefopam, and ananticonvulsant drug which functions as an anti-shivering mechanism, andwhich can be administered prior to, simultaneous with, or subsequent toinitiation of the temperature lowering step.

[0063] Before describing detailed embodiments of the invention, it willbe useful to set forth definitions that are used in describing theinvention. The definitions set forth apply only to the terms as they areused in this patent and may not be applicable to the same terms as usedelsewhere, for example in scientific literature or other patents orapplications including other applications by these inventors or assignedto common owners. Additionally, when examples are given, they areintended to be exemplary only and not to be restrictive. For example,when an example is said to “include” a specific feature, that isintended to imply that it may have that feature but not that suchexamples are limited to those that include that feature.

[0064] The term “set point temperature” is used herein to refer to thetemperature that the body attempts to maintain through thethermoregulatory responses. The set point temperature can vary bothbetween individuals and within the same individual at different times.For example, in a healthy individual, the set point temperature isusually about 37° C. However, the set point temperature can be changed,for example when an individual is ill and the body develops a fever. Inthat instance the thermoregulatory system actually works to maintain ahigher than normal body temperature. Thus, in such circumstances the setpoint temperature can be higher than 37° C.

[0065] As used herein, the term “lowered temperature state” is intendedto mean a state where the temperature of all or a portion of a patient'sbody has been reduced to a temperature below the set point temperature.The term ” lowered temperature state” includes, for example, thelowering of an elevated body temperature to normothermic (about 37° C.).Here, the set point temperature is a fever and the body temperature isreduced to 37° C., a temperature below the fevered set pointtemperature. More typically, the term “reduced temperature state” refersto a “hypothermic state”, which can occur when the normal bodytemperature of 37° C. is reduced to a lower temperature, i.e., the setpoint temperature is a normal 37° C. state and the body temperature isreduced to below 37° C. Typically, hypothermia may be induced bylowering the patient's temperature until it is about 32° C. It isunderstood, however, that these temperature values provide a usefulbasis for discussion but definitions vary widely in the medicalliterature.

[0066] As used herein the term “normothermic” is intended to mean atemperature of about 37° C. (98.6° F.).

[0067] As used herein, the term “shivering” is intended to mean theuncontrolled muscle movement that an animal typically experiences whencold that does not result in controlled and coordinated movement of theorganism, and includes, for example, trembling and quaking. Moreprecisely, the term is used to mean the, trembling or quaking that ananimal experiences when it's body temperature falls to a certaintemperature below its set point temperature, said “certain temperature”sometimes being referred to as the “shivering threshold”.

[0068] As used herein, the term “reduce” as it pertains to shivering isintended to include minimizing shivering to a noticeable degree,eliminating shivering in its entirety and preventing shivering fromstarting.

[0069] As used herein, the term “patient” will typically be mammalian,and most commonly a human. As such, the term “therapeutically effectiveamount” is intended to mean a dosage sufficient to reduce shivering inthe patient being treated, and will vary depending upon various factorssuch as the patient species, the particular drug used, e.g theα2-adrenoreceptor agonist, non-opiod analgesic monoamine uptakeinhibitor, neuropeptide, nefopam or anticonvulsant drugused, thepatient's age, weight and other characteristics, including anyindividual sensitivity.

[0070] In general, the method of the invention relates to controllingthe temperature of all or a portion of a patient's body to a temperaturebelow its set point temperature, while reducing shivering. One exampleof the method of the invention comprises the steps of:(a) sensing thetemperature of all or a portion of the patient's body; (b) generating asignal based upon the sensed temperature; (c) controlling thetemperature of all or a portion of the patient's body based upon thesignal; and (d) reducing or eliminating shivering by placing a warmingblanket over the surface of the patient and administering an agentselected from the group consisting of α2-adrenoreceptor agonists,non-opiod analgesic monoamine uptake inhibitors, neuropeptides, nefopam,and an anticonvulsant drug to the patient.

[0071] As used herein, the term “controlling the temperature” isintended to include lowering the temperature below the set pointtemperature, raising the temperature from an initial temperature belowthe set point temperature, raising the temperature at a predeterminedrate or increase, and maintaining the temperature at a stabletemperature below the set point temperature. Such stable temperature canbe, for example, normothermia.

[0072] An example of one such method comprises the steps of: (a)positioning a heat exchange device within the patient and in heatexchanging proximity to body fluid such as blood; (b) utilizing thedevice to lower the temperature of said body fluid to a sufficientdegree and for a sufficient duration to alter the temperature of saidbody; and (c) reducing or eliminating shivering by placing a warmingblanket over the surface of the patient and administering an agentselected from the group consisting of α2-adrenoreceptor agonists,non-opiod analgesic monoamine uptake inhibitors, neuropeptides, nefopam,and an anticonvulsant drug to the patient. As used herein, the term“utilize” is intended to include, for example, activating the device,adjusting the thermal output of the device and deactivating the device.The positioning step can involve, for example, placing a heat exchangedevice having a heat exchange region into the vascular system of thepatient. The temperature of the heat exchange region is then controlledfor a sufficient time to affect the temperature of the patient.

[0073] Although the methods of the invention may be used to cool theentire patient's body, they may be useful in cooling a specified portionof a patient's body. For example, the methods of the invention may coolthe brain or a portion thereof to deter neural damage following a strokeor other insult (e.g., period of ischemia, period of hypoxia,hemorrhage, trauma, etc.). In this manner, the heat exchange devicewould be positioned in a blood vessel which leads to the brain, such asthe right common carotid artery, left common carotid artery, innominateartery, right internal carotid artery, left internal carotid artery, andso forth. Alternatively, the heat exchange device may be positioned in alarge vein such as the inferior vena cava and heat removed from theblood for a sufficient length of time to cool the entire body and thuscool the neural tissue, such as the brain and spinal cord, as well.

[0074] It may also be desirable to cool the entire patient's body suchas a febrile patient. For example, in stroke patients who have becomefebrile, it may be therapeutically desirable to reduce the body'stemperature to normothermic. In particular, the methods of the inventionfind utility in treating patients that have suffered a stroke, sincestoke patients often develop a fever. Even a slight fever in these casesis correlated with much worse outcomes than in patients who do not havea fever. In such cases, it is advantageous to maintain the patient atnormothermia. However, since patient's with a fever often have their setpoint reset to a temperature above normothermia, even reducing thepatient's temperature to normal in those cases may trigger shiveringwith the attendant problems.

[0075] The methods of the invention serve to lower the temperature to atemperature below its set point temperature, while simultaneouslyinactivating the thermoregulatory response by means of an anti-shiveringmechanism. The order of the steps of the method can be conducted severalways in that the α2-adrenoreceptor agonist, non-opiod analgesicmonoamine uptake inhibitor, neuropeptide, nefopam and an anticonvulsantdrug can be administered prior to, simultaneous with, or subsequent toinitiation of the temperature lowering step. In this manner, theα2-adrenoreceptor agonist, non-opiod analgesic monoamine uptakeinhibitor or neuropeptide can be administered to the patient: prior tocontrolling the body temperature, for example, prior to positioning aheat exchange device; after positioning the device but beforeutilization; simultaneous with the utilization step (b); or subsequentto the utilization step.

[0076] Several acceptable methods are illustrated in FIG. 23 in the formof a flow chart. For sequential administration routes, theα2-adrenoreceptor agonist, non-opiod analgesic monoamine uptakeinhibitor, neuropeptides, nefopam and an anticonvulsant drug can beadministered before positioning the heat exchange device (200), afterthe device has been positioned (202), after the device has beenactivated (204), or after the device has been deactivated (206), thelatter being useful if it is desired to administer the anti-shiveringmechanism after the body has already been cooled to the desiredtemperature. For simultaneous administration routes, theα2-adrenoreceptor agonist, non-opiod analgesic monoamine uptakeinhibitor neuropeptide, nefopam, and an anticonvulsant drug can beadministered simultaneously with the positioning of the heat exchangedevice (208) or while the device is activated (210). The invention alsocontemplates administering the α2-adrenoreceptor agonist, non-opiodanalgesic monoamine uptake inhibitor, neuropeptides, nefopam and ananticonvulsant drug in any combination of the aforementioned sequentialand simultaneous routes.

[0077] In another aspect of the invention, a method of controlling thetemperature of a patient below the set point temperature comprises thesteps of: (a) employing internal in vivo core temperature regulation;and (b) administration of an agent selected from the group consisting ofα2-adrenoreceptor agonists, non-opiod analgesic monoamine uptakeinhibitors, neuropeptides, nefopam and an anticonvulsant drug. One meansof employing internal in vivo core temperature regulation comprisesplacing a heat exchange device in the blood vessels of the patient,where the heat exchange device has a heat exchange region that is incontact with the flowing blood of the patient. The temperature of theheat exchange region can then be controlled for a sufficient time toaffect the temperature of the patient. The heat exchange device may be acatheter having a shaft for the circulation of heat exchange fluidtherein. The heat exchange region can be a balloon; and the temperatureof the heat exchange region is controlled by circulation of heatexchange fluid through the shaft and the interior of said balloon.

[0078] As noted above, the cooling aspect of the invention operates tocool the entire patient's body to lower the patient's body temperature,or to cool a portion of the patient's body, for example, to minimizedamage to a particular body tissue.

[0079] In a preferred method of the invention, the body temperature islowered by cooling a body fluid in situ for a sufficient length of timeto lower the temperature by the desired amount, while reducing patientshivering that typically accompanies such cooling by placing a warmingblanket over the surface of the patient and administering anα2-adrenoreceptor agonist, non-opiod analgesic monoamine uptakeinhibitor, neuropeptides, nefopam and an anticonvulsant drug. Typicalbody fluids include, blood, cerebral spinal fluid, peritoneal fluid orthe like, but will typically be blood. In addition, the methods of theinvention will generally result in in situ cooling of target bodytissues and organs, either by cooling body fluid directed to the tissue,as in cooling the brain by cooling blood flowing through the carotidartery, or by cooling the whole body which results in cooling the targettissue. Typical body tissues and organs that may be the target tissueinclude, neural tissue, brain, heart, spinal cord tissue, kidney, liverand the like, but will typically be the heart and the brain.

[0080] The heat exchange device itself may have a temperature within therange of 0 to 42° C. By controlling the temperature of the portion ofthe device that is in heat exchanging proximity to the body fluid sothat a temperature differential (ΔT) exists between the heat exchangedevice and the body fluid, heat is transferred between the device andthe body fluid. For example, when the body temperature is lowered bycooling blood, the heat exchange device is positioned within a bloodvessel and maintained with a temperature below that of the blood flowingpast the heat exchange device so that heat is transferred between thedevice and blood flowing through the vessel. Blood flows in heattransfer proximity to the heat exchange device and is cooled. Bycontinuing to cool fluid flowing past the heat exchanger in sufficientvolume and for a sufficient length of time, the temperature of thepatient is reduced. The methods of the invention are suited to lower thebody temperature of a patient by as much as 9° C. It is not expected toreduce the patient's body temperature to less than 28° C., andpreferably not lower than 32° C.

[0081] Another important aspect of the instant invention is that thetemperature of the patient's body or portion thereof can be reducedcontrollably, thus avoiding the problems associated with cooling apatient too rapidly, or below a desired temperature. Likewise, when ahypothermic patient is warmed, the combination of an internal heatexchange device controlled by feedback with the anti-shivering agentthat reduces the body's shivering and thus allow more precise controlover the patient's temperature, permits a more gradual and gentlewarming of the patient. It will be readily seen that if a patient ismaintained at a reduced temperature below the set point temperature andparticularly below the shivering threshold, the administration of theanti-shivering agent in combination with feed-back controlled in vivoheat exchange permits a more effective temperature control of thepatient. In particular, when inducing hypothermia, a target tissue canbe cooled to the desired temperature and that temperature maintained bycontrolling the heat exchange device. This is shown schematically inFIG. 23, where feedback information is obtained from the patient, forexample, the patient's temperature is measured (either the temperatureof the entire body, the target tissue or fluid), and that feedbackinformation is used in a feedback system (212) to continually control oradjust the output of the heat exchange device. In this manner, thefeedback system may be used to achieve or maintain, for example apre-determined body or body fluid temperature, a pre-determined heatexchange device temperature or a pre-determined ΔT. This is optional,however. The methods of the invention are well suited for use where thedevice may operate in a simple on-off mode. That is, it may operate atfull power until deactivated (214) or where the device is activated,adjusted one or more times during its operation (216) and thendeactivated (218). Feedback information can also be obtained from thepatient regarding the amount of shivering being experienced and thisfeedback system (220) can be used to continually control or adjust theadministration of the anti-shivering agent.

[0082] Generally the methods of the invention will involve affecting thetemperature of the entire body, but different regions may becontrollably maintained at temperatures different from each other, forexample, by controlling different heat exchange devices at differentlocations with the patient's body.

[0083] In one embodiment of the invention, the heat exchange device ispositioned within the patient, preferably intravascularly. For example,the heat exchange device, such as a catheter, is inserted through apuncture or incision into a fluid containing portion of the patient'sbody, for example, percutaneously into a blood vessel. An internallypositioned device, i.e., core cooling, is advantageous as it circumventsvasoconstriction. Accordingly, in one embodiment of the invention, amethod of controlling a mammalian patient's temperature below thepatient's set point temperature, while inhibiting the patient'sthermoregulatory responses, comprises the steps of (a) positioning aheat exchange device in a blood vessel, for example a blood vesselleading to the vena cava or brain; (b) utilizing the device to decreasethe temperature of blood which passes in heat exchanging proximity tothe heat exchange device; and (c) administering an agent selected fromthe group consisting of α2-adrenoreceptor agonists, non-opiod analgesicmonoamine uptake inhibitors, neuropeptides, nefopam and ananticonvulsant drug to the patient.

[0084] The heat exchange device can have the configuration of a numberof medical devices that are well known in the art. Although a catheteris preferred, it is understood that any other suitable means of coolingthe body and/or target fluid or tissue is suitable for use in theinstant invention, and that the particular catheter configurationsdescribed herein are intended to be exemplary and not limiting in anymanner. The preferred heat exchange mechanism involves heat exchanger incontact with a body fluid or tissue on its external surface, the heatexchanger being chilled or heated on its internal surface by circulationof a chilled fluid which is preferably sterile saline or otherbiocompatible fluid having appropriate heat transfer characteristics.

[0085] In one embodiment of the invention, a method of controlling apatient's temperature comprises utilizing a heat exchange device whichis a catheter. In addition, an anti-shivering agent is administered tothe patient to reduce shivering. A suitable catheter comprises anelongate flexible catheter having a heat exchanger which is capable ofexchanging heat between blood or other body fluid which flow in heatexchanging proximity thereto. For example, a catheter having a heatexchanger or heat exchange region which may be, for example, a balloonwith fins, is inserted through a puncture or incision into a fluidcontaining portion of the patients body, for example, a blood vessel.The temperature of the balloon is controlled by the circulation of aheat exchange fluid through the interior of the balloon. Blood flows inheat transfer proximity past the heat exchanger. Heat exchange proximityrequires sufficient proximity for effective heat exchange to occur anddepends on such factors as the chemical and physical make-up of theblood, the rate of flow past the heat exchange surface, the pattern ofblood flow past the heat exchanger, (laminar flow, turbulent flow, andthe like), the difference in temperature between the heat exchangesurface and the blood, the material of which the heat exchange surfaceis made, and the proximity between the heat exchange surface and theblood. By continuing to cool fluid flowing in heat transfer proximityfor a sufficient length of time, the body temperature of the patient isaltered.

Anti-Shivering Mechanism

[0086] As used herein, the term “anti-shivering mechanism” is intendedto mean the administration of an anti-shivering agent selected from thegroup consisting of α2-adrenoreceptor agonists, non-opiod analgesicmonoamine uptake inhibitors , neuropeptides, nefopam and ananticonvulsant drug to a patient.

[0087] As used herein, the terms “α2-adrenoreceptor agonist”, “non-opiodanalgesic monoamine uptake inhibitor” and “neuropeptide” are intended tomean any biologically active agent or drug or combination of agents ordrugs within that class, that is administered to a patient for thepurpose of reducing shivering. The term is also intended to includepharmaceutically acceptable salts or variants of such agents whichretain the biological effectiveness of the agents themselves. Such saltsare often preferred as the salt form may have better solubility,increased duration of action, and so forth. Suitable salts are wellknown to those of skill in the art and may include the hydrochloride,methanesulfonate, mesylate, maleate, decanoate, enanthate, succinate,lactate, sulfate, and quaternary ammonium salts. Likewise, nefopam, andanticonvulsant drugs are intended to refer to those drugs, acceptablesalts, and other prodructs that may be useful to enhance administrationof the drug. For example, the intravenous administration of phenytoin isgenerally accomplished by adminstration of fosphenytoin which is aprodrug which is metaboloized into its active metabolite, phenytoin.

[0088] The α2-adrenoreceptor agonists suitable for use in the methods ofthe invention, include by way of illustration and not limitation,dexmedetomidine; detomidine; medetomidine; clonidine; bromonidine;tizanidine; mivazerol; guanfacine; oxymetazonline;(R)-(-)-3′-(2-amino-1-hydroxyethyl)-4′-fluoro-methanesulfoanilide;2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline;5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine;5,6,7,8-tetrahydro-6-(2-propenyl)-4H-thiazolo[4,5-d]azepin-2-amine;6-ethyl-5,6,7,8-tetrahydro-4H-oxaazolo[4,5-d]azepin-2-amine;5,6-dihydroxyl-1,2,3,4-tetrahydro-1-naphyl-imidazoline; andpharmaceutically acceptable salts thereof.

[0089] The non-opiod analgesic monoamine uptake inhibitors suitable foruse in the methods of the invention, include by way of illustration andnot limitation, nefopam; tramadol; and pharmaceutically acceptable saltsthereof.

[0090] The neuropeptides suitable for use in the methods of theinvention, include by way of illustration and not limitation,neurotensin; neurotensin analogs; bombesin; neuromedin; dermorphin;D-ala-deltorphin; and pharmaceutically acceptable variants thereof.

[0091] In most cases, however, when administered alone, a high dosagemay be required to achieve a desired temperature drop. In the instantinvention, the reduced temperature state is induced by a heat exchangedevice, such as a cooling catheter, while the anti-shivering agent isused to overcome shivering. Several agents from different classes mayalso be administered in combination, for example an α2-adrenoreceptoragonist may be administered in combination with a neuropeptide. In thismanner, small non-toxic dosages can be administered to achieve thedesired anti-shivering results. Accordingly, the suitability of ananti-shivering agent for use in the methods described herein dependsupon its ability to suppress the thermoregulatory mechanisms to reduceshivering during cooling and thereafter while the patient is maintainedat a temperature that would otherwise produce shivering.

[0092] As noted above, pharmaceutically acceptable salts of theα2-adrenoreceptor agonist are also well suited for use in the methods ofthe invention. These include dexmedetomidine hydrochloride, and soforth. Pharmaceutically acceptable salts of the non-opiod analgesicmonoamine uptake inhibitors are also well suited for use in the methodsof the invention as are pharmaceutically acceptable variants of theneuropeptides.

[0093] Typically, the anti-shivering agent or pharmaceuticallyacceptable salt or variant thereof will be administered in combinationwith a pharmaceutically acceptable carrier.

[0094] A particularly well-suited α2-adrenoreceptor agonist isdexmedetomidine and its salt, dexmedetomidine hydrochloride (sold byAbbott Laboratories under the mark Precedx™). Exposure to temperatureextremes is often associated with increases in circulating catecholamineconcentrations. Dexmedetomidine is of particular interest since it actsas an anti-shivering agent, as well as acting to counter the surge incatecholamine levels that can occur when a patient's body temperaturedrops below its set point temperature. In addition, dexmedetomidine, aswell as nefopam and neurotensin, causes minimal depression of therespiratory drive in patients, as opposed to other agents such asopiods.

[0095] The administration of anticonvulsant medications in the shiveringsuppression context may generally be accomplished by the intravenousadministration of an anticonvulsant pro-drug, such as fosphenytoin, atleast 15 minutes before the shivering suppression is desired.Anticonvulsant pro-drugs form active metabolites within the body thatprovide the desired anticonvulsant effects. For example, fosphenytoin ismetabolized to phenytoin with the resultant anti-shivering propertiesbeing exhibited when a sufficient level of the phenytoin metabolite isdeveloped in the body. A dosage of fosphenytoin that has been found tobe effective is set out below.

Dosage of Anti-Shivering Agents

[0096] A therapeutically effective amount of the anti-shivering agentselected from the group consisting of α2-adrenoreceptor agonists,non-opiod analgesic monoamine uptake inhibitors and neuropeptides is tobe administered, which is intended to be a dosage sufficient to reduceor eliminate shivering in the patient being treated. The actual dosageamount will vary depending upon the patient's age and weight, along withthe dosage form and α2-adrenoreceptor agonist, non-opiod analgesicmonoamine uptake inhibitor or neuropeptide selected. Generally a typicaldosage will be within the range of about 0.5 to 10 mg/kg of body weight,preferably about 0.5 to 2.0 mg/kg of body weight, and most preferablyabout 0.5 to 1.0 mg/kg of body weight. It is believed that 0.1 mg to 5.0g of the anti-shivering agent will provide a therapeutic effect in themethods of the invention.

[0097] The preferred dosage will be dependent upon the time periodduring which the patient's body temperature is being reduced (eitherfrom a fevered state to normothermic or from normothermic to ahypothermic state), along with the actual drop in patient temperaturethat will be experienced during this procedure. Accordingly, for themethods of the instant invention, the amount of anti-shivering agentadministered should be sufficient to reduce shivering while the bodytemperature is being reduced and maintained at the lower temperature,which may be 24-72 hours.

[0098] It is important to note that the amount of anti-shivering agentrequired for maintaining a patient at a predetermined temperaturewithout shivering may be different than the amount required when thepatient's temperature is being lowered to reach a predeterminedtemperature. For example, a patient may require a different dose of ananti-shivering agent, generally more, to prevent shivering during activecooling than the dose needed to prevent shivering while being maintainedat the target temperature. For this reason, it may be desirable tomonitor the level of patient shivering, as shown in FIG. 23, so that theadministration of the anti-shivering agent can be adjusted accordingly.Another factor to consider when selecting a dosage is the rate at whichthe temperature of the patient is being changed, i.e. the rate ofcooling, since this may affect the shivering response and thus the doseof anti-shivering agent that is appropriate. Likewise, the shiveringresponse may be different at different temperatures below the shiveringthreshold. For example, a patient might shiver more vigorously at 34° C.than at 32° C. Additionally, of course, individuals will vary widely intheir shivering thresholds, the vigor of their shivering response, andtheir sensitivity to the agent. The various α2-adrenoreceptor agonists,non-opiod analgesic monoamine uptake inhibitors and neuropeptide mayalso vary in strength depending on their individual purity andpreparation. For all these reasons, dosage recommendations herein aremerely suggestive and by no means comprehensive or restrictive.

[0099] Fosphenytoin has sometimes been administered as ananti-convulsant drug. As such an appropriate dosage was 20 mg PE/Kg. (75mg/mL of fosphenytoin sodium is equivalent to 50 mg/mL of the activemetabolite, phenytoin sodium. As is common in the art, dosage and rateof administration are usually expressed in the physical equivalent (PE)of the active ingredient.) However, one such dose was found not to beeffective at eliminating shivering, and two doses were administered backto back and were found to be effective. Thus the effectiveanti-shivering dosage is about double the amount effective as ananti-convuslant dosage. The timing and means of administration are setforth in the following sections.

Route of Administration of Anti-Shivering Agents

[0100] There are numerous routes and formulations by which theα2-adrenoreceptor agonist, non-opiod analgesic monoamine uptakeinhibitor or neuropeptide can be administered to the patient undergoingthe hypothermia inducing procedures described herein. For example, theanti-shivering agent can be administered either alone or in combinationwith other pharmaceutically acceptable excipients, including solid,semi-solid, liquid or aerosol dosage forms, such as, for example,tablets, capsules, powders, liquids, injectables, suspensions,suppositories, aerosols or the like. The anti-shivering agent can alsobe administered in sustained or controlled release dosage forms,including depot injections, osmotic pumps, pills, transdermal (includingelectrotransport) patches, and the like, for the prolongedadministration of the anti-shivering agent at a predetermined rate. Thecompositions will typically include a conventional pharmaceuticallyacceptable carrier or excipient and the anti-shivering agent or apharmaceutically acceptable salt thereof. In addition, the compositionmay include other medicinal agents, pharmaceutical agents, carriers,adjuvants, and so forth. Generally, depending on the intended mode ofadministration, the pharmaceutically acceptable composition will containabout 0.1-90.0% by weight, preferably about 0.5-50.0 wt %, of theanti-shivering agent or its salt, the remainder being suitablepharmaceutical excipients, carriers, etc. See, for example, “Remington'sPharmaceutical Sciences” (Mack Publishing Company, Pennsylvania, 18thEdition, 1990) and “Goodman & Gilman's the Pharmacological Basis ofTherapeutics”, (Goodman, et al., Eds., 9th edition, 1996) for extensivediscussions on the preparation and composition of various formulationssuitable for use in administering the anti-shivering agents describedherein.

[0101] The anti-shivering agent can be administered orally,transdermally, directly into the cerebrospinal fluid (e.g.,intracereboventricualrly or intracisternally) or parenterally(intramuscularly or intravenously), with intramuscular or intravenousinjection being the preferred routes of administration.

[0102] For oral administration, the compositions may take the form of asolution, suspension, tablet, capsule, powder, sustained releaseformulation, and the like. A typical pharmaceutically acceptablecomposition is formed by the incorporation of any of the normallyemployed excipients, such as, for example, a diluent (lactose, sucrose,glucose, dicalcium phosphate), lubricant (magnesium stearate),disintegrant (croscarmellose sodium), binder (starch, gum acacia,polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives),mannitol, povidone, sodium saccharine, talcum, magnesium carbonate, andthe like. Such compositions take the form of solutions, suspensions,tablets, dispersible tablets, pills, capsules, powders, sustainedrelease formulations and the like.

[0103] Liquid pharmaceutically administrable compositions can, forexample, be prepared by dissolving or dispersing an anti-shivering agentand optional pharmaceutical adjuvants in a carrier, such as, forexample, water, saline, aqueous dextrose, glycerol, glycols, ethanol,and the like, to thereby form a solution or suspension. If desired, thepharmaceutical composition may also contain minor amounts of nontoxicauxiliary substances such as wetting agents, suspending agents,emulsifying agents, or solubilizing agents, pH buffering agents and thelike, for example, sodium acetate, sodium citrate, cyclodextrinederivatives, polyoxyethylene, sorbitan monolaurate or stearate,triethanolamine oleate, etc. Liquid or semi-solid oral formulations canalso be prepared by dissolving or dispersing the anti-shivering agent orits salt in vegetable oils, glycols, triglycerides, propylene glycolesters (e.g. propylene carbonate) and the like, and encapsulating thesesolutions or suspensions in hard or soft gelatin capsule shells toprovide a solid dosage form.

[0104] Formulations for parenteral injection can be prepared inconventional forms, either as liquid solutions or suspensions, solidforms suitable for solution or suspension in liquid prior to injection,or as emulsions. Formulations of 0.1 to 10 wt % anti-shivering agent insolution are acceptable, with 2.5 wt % being typical.

[0105] Fosphenytoin may be administered intravenously at a rate of about150 MgPE/min. As mentioned above, about 75 mg of fosphenotoin sodium isequivalent to 50 m g of phenotoin so this translates to a rate ofadministration of about 225 mg/min of fosphenotoin.

Timing of Administration of the Anti-Shivering Agent

[0106] When inducing hypothermia, it is preferred to have therapeuticlevels of the α2-adrenoreceptor agonist, non-opiod analgesic monoamineuptake inhibitor or neuropeptide anti-shivering agent in the bloodstream or maintenance of the skin temperature already established bywarming the skin, while the heat exchange device is being used to lowerthe patient's core temperature. Accordingly, the preferred methods ofthe invention contemplate administration of the anti-shivering agentprior to initiation of the cooling step. When controlling the rate ofheating of an already hypothermic patient, or when maintaininghypothermia at a stable temperature below the shivering threshold, it isalso preferable to have therapeutic levels of the anti-shivering agentin the blood stream or the skin temperature already being maintained bywarming the skin. This can be accomplished by administering a bolusdosage to achieve the desired therapeutic level of anti-shivering agentin the blood, which can then be subsequently maintained by periodic orcontinuous administering the anti-shivering agent. The anti-shiveringagent may be administered periodically at a larger dose, for exampleintramuscular, or can be administered continuously at a smaller dose,for example intravenously.

[0107] The anti-shivering agent may be administered prior to positioningthe heat exchange device, before the cooling step commences,simultaneous with the cooling step, which can commence at the time thedevice is inserted or applied externally to the patient or at the timethat the heat exchange device is activated, or at a point in timesubsequent to the initiation of the cooling step. Yet another embodimentcontemplates continuing to administer the anti-shivering agent for sometime after the heat exchange device has ceased to operate. As notedabove, a single one-time dosage of agent, several periodic dosages ofagent administered at set time intervals, continuous administration ofagent, or a combination of these are also contemplated. The actualtiming of administration of the anti-shivering agent is best illustratedin FIG. 23, which shows the numerous points at which the anti-shiveringagent can be administered, either sequentially or simultaneously withthe other steps in the methods of the invention.

Heat Exchange Devices

[0108] The heat exchange device itself is preferably a catheter whichcomprises at least one fluid lumen through which a thermal exchangefluid may be circulated, a heat exchanger and a working lumen extendingfrom outside the patient through at least part of the catheter that isinserted into the patient. An example of such a catheter may be anelongate catheter having a proximal end and a distal end, where theentire length of said flexible catheter is defined as the distance fromits proximal end to its distal end, and comprising at least one fluidlumen through which a thermal exchange fluid may be circulated, a heatexchanger with heat exchange fins located at a first location on thecatheter, and a working lumen extending from outside the patient throughat least part of the catheter that is inserted into the patient.

[0109] The heat exchanger operates to exchange heat between blood whichflows in heat exchanging proximity to the heat exchanger and a thermalexchange fluid which is circulated through the catheter. The firstlocation at which the heat exchanger is located may constitute less thanthe entire length of the catheter, and is typically at or near thedistal end of the catheter. The heat exchanger may specifically comprisea balloon or other structure through which the thermal exchange fluidmay circulate, and the heat exchange fins may be a plurality of lobes ofthe balloon or other surface area increasing projections such asoutwardly extending protuberances, ribs, filaments of a multi-filamentdevice, curved or undulating surfaces, etc., that enhance the efficiencywith which heat exchange occurs.

[0110] The invention also contemplates a means for controlling the heatexchange device so that a predetermined temperature is established andmaintained. For example, a control system can monitor body temperatureand the device is then controlled in response to the body temperature.In this manner, the device can be modulated or shut off when thepatient's body or target region reaches a pre-selected temperature, andsimilarly, can be modulated, for example turned on, when the temperaturedeviates from the pre-selected temperature.

[0111] A significantly more sophisticated and automatic control overtemperature regulation is possible. Examples of such control systems areshown in FIG. 24 and FIG. 25. In the control system, feedback from thepatient's body is obtained by one or more temperature sensors attachedto the patient. Examples include an esophageal temperature probe 222, atympanic temperature probe 224, a skin temperature probe 226, a rectaltemperature probe 228, or other appropriate sensors as is well known inthe art. These probes generate signals that represent the temperaturesensed and transmit those signals over a plurality of wires 230 to acontrol unit 232, one embodiment of which is illustrated in FIG. 25. Thecontrol unit receives the temperature signals and controls the heatexchange region 234 of the heat exchange catheter 236 in responsethereto.

[0112]FIG. 25 illustrates another embodiment of a control unit 250 mayinclude a programmable computer 238, a thermoelectric heater/cooler 240,a supply of heat exchange fluid 242, and a pump 244. The pump may pumpthe heat exchange fluid through the supply source, for example, a bag242 over the thermoelectric heater/cooler to alter the temperature inthe fluid. The fluid may be pumped from an inlet tube 246 received fromthe heat exchange catheter, through the bag and back to the heatexchange catheter through the outlet tube 248. In response to thetemperature sensed, the controller may control the pump rate, or maycontrol the temperature of the thermoelectric heater/cooler.

[0113] In one embodiment, the control unit is programmed to control theheat exchange catheter to reach and maintain a target temperature. Thesupply of heat exchange fluid is a closed loop of heat exchange fluidcirculating through the catheter inside the patient and external of thepatient through the bag of fluid positioned adjacent the thermoelectricheater/cooler. As the sensed temperature of the patient approaches thetarget temperature, the control unit may adjust the temperature of thethermoelectric heater/cooler to approach the target temperature. Forexample, if the computer was programmed to control the patient'stemperature at 32° C., the thermoelectric cooler might originally be ata temperature of near 0° C., and thus the temperature of the heatexchange fluid flowing within the balloon would be about 0° C. However,as the temperature of the patient fell and began to approach 32° C., thecontrol unit would act to increase the temperature of the thermoelectricheater/cooler (by altering the current flowing therethrough, forexample) so that it began to warm toward 32° C. It has been found that atemperature of the heat exchange fluid of about 30° C. will removeapproximately the amount of heat that a body at rest at 32° C.generates, so as the body temperature reaches the target temperature of32° C., the control unit will gradually control the thermoelectricheater/cooler to level off at a constant temperature of 30° C.

[0114] Similarly, the control unit may regulate the rate of temperaturechange. A rate of change of patient temperature may be programmed intothe computer of the controller. If the sensed temperature of the patientis changing more rapidly or more slowly than the programmed rate, thetemperature of the heat exchange fluid may be controlled by controllingthe thermoelectric heater/cooler and thus removing or adding heatthrough the heat exchange catheter to the blood of the patient inappropriate amounts to control the rate of temperature change in thepatient.

[0115] It may be readily seen that many variations on this control unitare possible without departing from the invention. For example, thecontrol unit may receive signals from one, two or more temperaturesensors, which would be included in the control system. Sensors of otherparameters than body temperature, such as pulse rate or blood pressureor the like, are within the contemplation of the invention, and may alsobe included in the control system. Likewise, the target temperature isonly one end point that may be desirable with the controller; the targetmay be some other bodily condition such as blood pressure, EEGcondition, and the like. Also the nature of the response of the controlunit which serves to control the heat exchanger may vary. It may be asimple as an on/off response. It may vary the rate of pumping, thetemperature of the thermoelectric plate, or any other suitable variableto control the heat exchanger.

[0116] If the anti-convulsant drug phenytoin is administered as theanti-shivering agent, it should be administered at least 15 minutesbefore the anti-shivering effect is desired. For example, if thepatient's temperature is normothermic, and it is estimated that theendovascular cooling system may take 15 minutes to cool the patient downto the shivering threshold, the fosphenytoin may be administeredsimultaneously with starting the cooling. As the procedure continues, ifthe anti-shivering effect is desired for an extended period, for examplemore than 4 hours, then additional parenteral administration of the drugmay be needed to maintain the necessary effective level, as long astoxic levels of the drug are avoided. The standard pharmaceuticalliterature gives the needed guidance regarding toxic level andcontraindications, and as mentioned above, about double the effectiveanti-convulsant dosage is effective as an anti-shivering agent.

Kits

[0117] Another aspect of the invention pertains to a kit for reducingthe temperature of a patient comprising (a) a heat exchange device and(b) an agent selected from the group consisting of α2-adrenoreceptoragonists, non-opiod analgesic monoamine uptake inhibitors andneuropeptides. The kit may contain instructions, as appropriate, both asto the operation of the device and the anti-shivering mechanism. The kitmay also include information pertaining to the storage and dosageinstructions for the agent, and so forth

[0118] For example, the kit may contain instructions for the properinsertion of the catheter into the vascular system as is well known inthe medical arts, for example by the Seldinger technique. Theinstructions may also contain a description of the proper use of theheat exchange catheter system, the proper target temperature for thepatient, and if the kit contains a control unit, the appropriate ramprates for heating and cooling the patient, as well as specificrecommendations for the use of the α2-adrenoreceptor agonist, non-opiodanalgesic monoamine uptake inhibitor or neuropeptide. The kit may or maynot contain the anti-shivering, but may contain a description of thepreferred α2-adrenoreceptor agonist, non-opiod analgesic monoamineuptake inhibitor or neuropeptide, for example a preferredα2-adrenoreceptor agonist, non-opiod analgesic monoamine uptakeinhibitor or neuropeptide selected from those set out above, andsuggestions as to dosage and methods of administration and the like. Theduration of administration of cooling and use of the anti-shiveringmechanism may also be set out.

[0119] In one embodiment of the kit, the heat exchange device is acatheter. A suitable catheter is an elongate catheter having a proximalend and a distal end, the entire length of the catheter being defined asthe distance from its proximal end to its distal end, and comprises (i)at least one fluid lumen through which a thermal exchange fluid may becirculated; (ii) a heat exchanger with heat exchange fins located at afirst location on the catheter; and (iii) a working lumen extending fromoutside the patient through at least part of the catheter that isinserted into the patient.

[0120] The kit can optionally include a control system that monitorsbody conditions, for example by measuring temperature, and controls theheat exchange device in response to the body conditions being monitored,such as turning off the device when the patient's body or target regionreaches a pre-selected temperature, or reactivating the device when thetemperature deviates from the pre-selected temperature. In addition, thekit may also comprise a second heat exchange device. This second devicemay serve to compliment the temperature lowering ability of the firstdevice, i.e., the second device may also serve to lower the temperatureof the body or portion thereof. Alternately, the second device may serveto increase the temperature of the patient's body or body portion. Thisis useful to provide heat in the event that the method of the inventionresults in a lower temperature than is desired, or if it is desired toconclude the therapy and raise the patient's temperature tonormothermic.

[0121] These and other methods of the invention are readily understoodin references to the figures described below. One embodiment of the heatexchange device suited for use in the methods of the invention isillustrated in FIG. 1, which shows the distal end 2 of a heat exchangedevice 4, which has been inserted through the patient's skin into ablood vessel 6. Blood flow through the vessel is indicated by a set offlow arrows. Preferably, the device is inserted into a relatively largeblood vessel, e.g., the inferior or superior vena cava, a femoral arteryor vein, a jugular artery or vein, or the aorta. Use of these vessels isadvantageous in that they are readily accessible, provide safe andconvenient insertion sites, and have relatively large volumes of bloodflowing through them. In general, large blood flow rates facilitate moreefficient heat transfer between the catheter and the blood. For example,the jugular vein may have a diameter of about 22 French, or a bit morethan 7 mm, where 1 French is 0.013 inches or 0.33 mm. A heat exchangedevice suitable for insertion into a vessel of this size can be madequite large relative to devices intended for insertion into smallervessels in the vascular system.

[0122] A particularly well suited heat exchange device is a catheter.Atherectomy or balloon angioplasty catheters, used to clear blockagesfrom the coronary artery and similar vessels, commonly have externaldiameters in the range between 2 to 8 French. In contrast, it isanticipated that a catheter useful in the methods of the instantinvention will typically have an external diameter of about 9French,although this dimension may obviously be varied a great deal withoutdeparting from the basic principles of the claimed invention. It isdesirable that the catheter or other heat exchange device be smallenough so that the puncture site can be entered using the percutaneousSeldinger technique, a technique well known to medical practitioners.Other techniques for inserting devices into the above mentioned bloodvessels are also well known among medical personnel.

[0123] Although a small diameter is chosen for the heat exchange device,this diameter is based upon the pre-insertion size, and is aimed atavoiding or minimizing vessel trauma. However, after the device isinserted in the vessel, its distal end can be expanded to any size solong as blood flow is not unduly impeded. Additionally, the femoralartery and vein and the jugular vein are all relatively long andstraight blood vessels. This will allow for the convenient insertion ofa device having a temperature controlled region of considerable length.This is of course advantageous in that more heat may be exchanged at agiven temperature for a device of a given diameter if the length of theheat transfer region is increased. Although the method of the presentinvention will probably be most commonly employed in a hospital, theprocedure need not be performed in an operating room. The method andapparatus are so simple that the device may be inserted and treatment tolower the patient's temperature and reduce shivering may begin even inan ambulance or in the field.

[0124] In general, the distal end 2 of the device may be cooled andmaintained at a temperature below the patient's body temperature. Bloodflowing through the vessel will therefore be cooled, and will then becirculated rapidly throughout the patient's circulatory system. Thebeneficial effect of cooling the patient's blood in the vicinity of thedevice will thereby be spread very quickly throughout the entire body ofthe patient.

[0125] The device depicted in FIG. 1. can utilize a variety of coolingmethods and can have numerous configurations that maximize its heatexchanging capability. A particularly well suited heat exchange deviceis a catheter, several configurations of which are described in detailin Ginsburg, U.S. Pat. No. 5,486,208 and Ginsburg, WO 98/26831, thedisclosures of which are incorporated herein by reference. For examplethe catheter can have a thermally conductive shaft running the length ofthe catheter body, made of a metal or other material having a highthermal conductivity. By cooling the proximal end of the shaft with anexternal cooling apparatus, heat will be caused to flow either into thedistal end of the shaft. Another cooling mechanism is provided by acatheter having two lumens running through it. Fluid flows from theproximal end of the catheter through in-flow lumen, through a heattransfer region, and back out through an out-flow lumen. By supplyingcooled fluid through the inflow lumen, heat may be transferred from thepatient's blood stream. Other embodiments and modifications for heattransfer other than by use of a heat exchanging fluid, e.g., resistance,including radio frequency, will occur to those skilled in the art.

[0126] The heat exchange devices useful in the methods of the inventionare preferably designed to optimize the rate of heat transfer betweenthe device and the body, tissue or fluid, for example with blood flowingthrough the vessel. While a large surface area is desirable in order toincreasing the effective heat transfer, care must be taken so that thedevice does not unduly restrict blood flow through the vessel. Thedevice can be fitted with a plurality of protrusions to maximize theheat transfer surface area, such as heat transfer vanes, radial fins orlongitudinal fins, or a multi-lobed balloon surface, collectivelyreferred to as heat exchange fins. In addition, the heat transfer regionof the device can be in the form of an expandable balloon, where theballoon remains inflated by, for example, the pressure difference in afluid flows through an inflow and outflow lumen.

[0127] It is estimated that heat exchange device whose surfacetemperature is controlled between about 1 to 15° C. and may provide abody core cooling rate of approximately 6 to 8° C. per hour in a patientof typical size, for example 115 pounds to 195 pounds and havingapproximately normal body temperature (37° C.). This estimate is highlydependent on a number of factors including the rate of blood flowthrough the vessel, the initial body temperature of the patient, theexternal surface area of the device through which heat is transferred,etc. The actual rate achieved may vary substantially from the aboveestimate. A more helpful estimation of temperature control of thepatient's body may be the wattage of energy [heat] removed from thebody. At normal blood flows over a catheter as described, as many as 300watts of energy may be removed from the blood. At rest, the human bodygenerates about 100 watts, but shivering may increase this amount to asmuch as five-fold. The ability to cool the body or control the body'stemperature is thus greatly enhanced by the administration ofanti-shivering agents while employing the cooling catheter. Other designconsiderations include a sensitive temperature sensor (see for example,FIG. 23) to closely monitor the temperature of the distal end of thedevice. While care should be taken to avoid freezing the tissue or fluidor inducing shock to the patient, this is rarely a concern. Since bloodis essentially water containing a number of suspended and dissolvedsubstances, its freezing point is somewhat below 0° C.

[0128] As may be readily appreciated, the rate of temperature alterationof the patient is greatly dependent on the amount of heat being removedfrom the blood. This in turn is greatly dependent on the difference intemperature between the blood and the surface of the heat exchangedevice (ΔT). When it is desirable to rapidly cool the patient, thetemperature of the device will be as cold as possible, for example bycooling a heat exchange fluid to almost 0° C., whereas when the operatorwants the patient's temperature to remain constant, for example after astate of hypothermia has been reached, only the amount of heat generatedby the body in excess of that which is normally lost to the environmentneeds to be removed. Thus it may be that the temperature of the balloonsurface may be maintained near 0° C. during cooling, and as the bodyreaches the required hypothermic level, the temperature of the heatexchange surface may be maintained just a few degrees below bodytemperature, for example at about 30° C. once the hypothermic state of32° C. has been reached.

[0129] In heating, it is conservatively accepted that a temperature of adevice in contact with the blood may be 42° C. without causing injury tothe blood. The ΔT in warming then will generally be less than when theheat exchanger is cooling the blood. If a carefully controlled rate ofwarming is desired, it will be readily appreciated that a large amountof metabolic heat generated by the body by shivering may overwhelm thesystem's ability to precisely control the rate of warming. Thereforeeven when warming a hypothermic patient, control of shivering isimportant.

[0130] Some preferred configurations of heat exchange devices areillustrated in the accompanying figures. In FIG. 2, a heat exchangeballoon catheter 10 with a finned balloon portion 12 may be positionedwithin at least a portion of the descending aorta 14 and a blood vessel16 conducting blood flow to the brain region. The balloon portion 12 istypically formed of material that is sufficiently thin to promoteeffective thermal transfer between heat exchange fluid within theballoon and blood flowing within heat exchange proximity of the balloon,but which is not excessively elastic to expand and unintentionallyobstruct a fluid passageway or blood vessel 16. A particularly suitablematerial is a thin, strong but relatively inelastic material such as PET(polyethylene terephthalate), which will allow for a predictable balloonconfiguration with adequate heat exchange properties. The catheter shaft18 of the thermal catheter 10 may be placed in a desired locationrelative to a selected body region or artery 16 by conventionaltechniques such as guiding catheters or steerable wire over-the-wiretechnique as known to those of ordinary skill in the field. The balloonportion 12 of the catheter 10 may support the closed-loop circulation ofa heat transfer fluid within the catheter and balloon as described inthe example set forth below. The increased surface area of the inflatedballoon may provide effective heat transfer within a body region bythermal conduction, and the configuration of the balloon may furtherpermit continued blood flow without substantial disruption by creatingchannels exterior of the balloon surface when the balloon is expanded.

[0131]FIG. 3 illustrates a heat exchange balloon 12 mounted on a shaft18, the balloon being defined by a longitudinal axis and a plurality ofheat transfer fins 20, 22, 24 and 26 projecting radially outward fromthe longitudinal axis of the catheter shaft. The heat transfer fins maybe formed, for example, as the lobes of a multi-lobed, collapsibleballoon. The shaft 18 is generally round and in this embodiment includesa working lumen 28 running through the shaft and open at the distal endof the catheter. Although in a preferred method, the anti-shiveringagent is administered by intramuscular or intravenous injection, it mayalso be administered through the central, or working lumen

[0132] In one embodiment of the invention, the working lumen is used forthe injection of the anti-shivering agent. The working lumen can alsoserve other functions. For example, along with being provided incombination with an anti-shivering agent, the catheter device mayfurther be provided in combination with a device (such as a guide wire,or embolectomy catheter) or other medicament (such as a thrombolyticagent, a barbiturate, an anticoagulant, a neuroprotectant, ananticonvulsant agent, an oxygenated perfusate, a vasodilator, an agentwhich prevents vasospasm, an agent to prevent platelet activation, andan agent to deter the adhesion of platelets), all of which can beinsertion through the working lumen. In addition, the working lumen maybe used for the injection of fluoroscopic dye, for the receipt of aguide wire, or as a guiding catheter for various diagnostic ortherapeutic devices including, for example, an angioplasty catheter, anembolectomy catheter, an occlusion member delivering catheter, anembolization member delivering catheter, an electro-cautery device, or amicrocatheter. As may be appreciated, the use of the lumen for onefunction does not prevent its subsequent use for another, so it may beused sequentially for several or even all of the uses described here.

[0133] The shaft exterior of the central lumen is shown in FIG. 4 andFIG. 6 as being divided by a web 30 into two channels, an inlet channel32 and an outlet channel 34. The shaft has inlet orifices 36, 38, 40(shown in FIG. 3) communicating between the inlet channel and theinterior of the balloon at the distal portion of the balloon. The shaftalso has outlet orifices 42, 44, 46 communicating between the interiorof the balloon and the outlet channel. A plug 48 is inserted in theoutlet channel between the inlet and the outlet orifices.

[0134] The balloon 12 may be made of, for example, a single sheet ofcollapsible thin plastic material 50, as shown in FIG. 5 sufficientlythin to allow for effective thermal exchange between a heat exchangefluid on the interior of the balloon and blood flowing over the exteriorof the balloon. Tacking the material to the shaft as shown at 52 mayform lobes of the balloon. Tacking the sheet of plastic to itself inappropriate locations as shown at 54 and 56 may further shape the lobes.The lobed shape of the balloon surface provides a significant surfacearea for heat exchange while also providing for continued flow past theballoon through the space between the lobes of the balloon.

[0135] In operation, heat exchange fluid (not shown) is pumped underpressure into the inlet channel 32. Suitable heat exchange fluidsinclude, by way of illustration and not limitation, sterile saline orother biocompatible fluid with appropriate heat transfercharacteristics. The heat exchange fluid flows down the inlet channeluntil it reaches the inlet orifices 36, 38, 40 at the distal end of theballoon. The fluid flows from the inlet channel into the interior of theballoon. It then flows in a proximal direction through the interior ofthe balloon until it reaches the outlet orifices 42, 44, 46 at theproximal end of the balloon. The heat exchange fluid then flows from theinterior of the balloon through the outlet orifices and into the outletchannel 34 where it then flows back down the shaft and out of the body.In this manner, the heat exchange fluid absorbs heat from the bloodflowing in heat transfer proximity to the balloon.

[0136] An alternative construction to the heat exchange balloon is shownin FIG. 7 wherein the heat exchange region is formed using a series ofthree collapsible balloon lobes 60, 62, 64 located around a centralcollapsible lumen 66. A proximal shaft 68 is formed having two channels,an inlet channel 70 and an outlet channel 72. The interior of the shaftis divided into two lumens by webs 74 and 76, as shown in FIG. 12, butthe lumens do not occupy equal portions of the interior of the shaft.The inlet channel occupies about ⅓ of the circumference of the interior;the outlet channel occupies about ⅔ of the circumference of the interiorfor reasons that will be explained below.

[0137] At the heat exchange region of the catheter, a transition 78 isformed between the shaft 68 and the tube 80 forming the centralcollapsible lumen 66. The outlet channel is plugged 82, as shown in FIG.10, the tube 80 is affixed over the shaft 68 by, for example gluing, atthe transition 78, and the shaft ends with the tube (not shown). In thisway, as shown in FIG. 9, the inlet channel in this portion of thecatheter occupies the entire circumference of the shaft. At the distalend of the balloon, shown in FIG. 8, inlet orifices 84, 86, 88 areformed between the inlet channel and the three collapsible balloons. Atthe proximal end of the heat exchange region, shown in FIG. 11, outletorifices 90, 92, 94 are formed between the interior of each balloon andthe outlet channel in the shaft. The configuration of the outlet channelis such that communication with the interior of each of the threeballoons is possible.

[0138] In operation, heat exchange fluid flows down the inlet channel inthe shaft 70, continues down lumen 66 to the distal end of the heatexchange region, exit the lumen through the inlet orifices 84, 86, 88 tothe interior lumens of the balloon lobes 96, 98, 100, travel back downeach of the three balloons and re-enter the shaft through the outletorifices 90, 92, 94 and then down the outlet channel 72 toward theproximal end of the catheter. In this way heat exchange fluid may becirculated through the three balloons to remove heat from the bloodflowing in heat transfer proximity to the balloons. The material fromwhich the balloons are made is made of a material that will permitsignificant thermal exchange between the heat exchange fluid on theinterior of the balloon and the body fluid such as blood flowing in heatexchange proximity to the surface of the balloon. A particularlysuitable material is very thin plastic material, which may also be madestrong enough to withstand the pressure necessary for adequate flow ofthe heat exchange fluid.

[0139]FIG. 13 illustrates another heat exchange catheter 102 suitablefor use in the method of this invention. The catheter 102 is constructedby attaching a balloon 104 having multiple lumens, over an inner shaftmember 106 in the manner described below. The assembled catheter 102(FIG. 13) has a four-lumen thin-walled balloon 104 (FIG. 15) which isattached over an inner shaft 106 (FIG. 14).

[0140] The cross-sectional view of the four-lumen balloon taken alongline 16-16 of FIG. 15 is shown in FIG. 16. The four-lumen thin-walledballoon 104 has three outer lumens 108, 110 and 112, which are woundaround an inner lumen 114 in a helical pattern. All four lumens are thinwalled balloons and each outer lumen shares a common thin wall segment(116, 118, 120) with the inner lumen 114. The balloon is approximatelytwenty-five centimeters long and when installed, both the proximal end122 and the distal end 124 are sealed around the shaft 106 in a fluidtight seal.

[0141] The shaft 106 is attached to a hub 126 at its proximal end. Thecross-sectional view of the proximal shaft at line 17-17 in FIG. 14 isshown at FIG. 17. The interior configuration of the shaft has threelumens: a guide wire lumen 128, an inflow lumen 130 and an outflow lumen132. It is understood however, the lumens 130 and 132 are referred to asinflow and outflow for illustrative purposes only. One of skill in theart may readily appreciate that lumen 132 may be used as the inflowlumen and lumen 130 may be used as the outflow lumen if the flow of theheat exchange fluid is reversed.

[0142] At the hub 126, the guide wire lumen 128 communicates with aguide wire port 134, the inflow lumen 130 is in fluid communication withan inflow port 136, and the outflow lumen 132 is in communication withan outflow port 138. Attached at the hub 126 and surrounding a portionof shaft 106 is a length of strain relief tubing 140 which may be, forexample, shrink tubing.

[0143] Between the strain relief tubing 140 and the proximal end 122 ofthe balloon, the shaft 106 is at the extruded outer diameter of about0.118 inches. The internal configuration is as shown in FIG. 17.Immediately proximal of the balloon attachment at its proximal end 22,the shaft has a necked down section 142. The outer diameter of the shaftis reduced to about 0.10 to 0.11 inches, but the internal configurationof the lumens is maintained. Compare, for example, the shaftcross-section shown in FIG. 17 with the cross-section shown in FIG. 18or the shaft cross-section shown in FIG. 20. This length of reduceddiameter shaft remains at approximately constant diameter between thefirst necked down section 142 and a second necked down section 144.

[0144] Immediately distal of the necked down section 142, a proximalballoon marker band 146 is attached around the shaft. The marker band146 is a radiopaque material such as a platinum band or radiopaquepaint, and is useful for locating the proximal end of the balloon bymeans of fluoroscopy while the catheter is within the body of thepatient.

[0145] At the marker band 146, the distal end of all four lobes of theballoon (108, 110, 112, 114) at 122 are fastened to the inner member122. This may be accomplished by folding the balloon down around theshaft, placing a sleeve, for example a short length of tubing, over theballoon and inserting adhesive, for example by wicking the adhesivearound the entire inner circumference of the sleeve. This simultaneouslyfastens the balloon down around the shaft, and creates a fluid tightseal at the proximal end of the balloon.

[0146] Distal of this seal, under the balloon, a window 148 is cutthrough the wall of the outflow lumen in the shaft. Juxtaposed to thatwindow, a plurality of slits 150 are cut into the wall of the outerballoon lumen, as shown in the cross-sectional view of FIG. 18 and theview in FIG. 19. Because the outer lumens are twined about the innerlumen in a helical fashion, each of the outer tubes passes over theoutflow lumen of the inner shaft member at a slightly different locationalong the length of the inner shaft, and where each of the other twoouter lumens pass over the outflow lumen of the shaft, other windows(152, 154) are cut into the outflow lumen and a plurality of slits (156,158) are cut into the outer lumen to fluidly connect the proximalportion of that outer lumen to the outflow lumen of the shaft. See, forexample, the section of FIG. 13 immediately distal of line 18-18. Inthis way the proximal portion of each outer lumen (108, 110, 112) isfluidly connected to the outflow lumen of the shaft.

[0147] Distal of the windows in the outflow lumen, the inner lumen 114of the fourlumen balloon is sealed around the shaft in a fluid tightseal. The outflow lumen 132 is plugged 160, and the wall to the inflowlumen is removed, as shown in FIG. 20. This may be accomplished by thenecked down section 144 to seal the outflow lumen shut (plug 160),removing the wall 162 of the inflow lumen 130, and affixing the wall ofthe inner lumen of the balloon around the entire outside 164 of theshaft with adhesive. The adhesive will also act as a plug to prevent theportion of the inner lumen proximal of the plug from being in fluidcommunication with the inner member distal of the plug.

[0148] Just distal of the necked down section 144, the guide wire lumen128 of the shaft may be terminated and joined to a guide wire tube 166.The tube 166 then continues to the distal end of the catheter. Theinflow lumen 130 is open into the inner lumen of the four-lobed balloonand thus in fluid communication with that lumen.

[0149] The distal end 124 of the balloon 104 including all four lumensof the balloon is sealed down around the guide wire tube 166 in a mannersimilar to the way the balloon is sealed at the proximal end around theshaft. This seals all four lumens of the balloon in a fluid tight seal.Just proximal of the seal, a plurality of slits 168 are cut into thecommon wall between each of the three outer lumens 108, 110, 112, of theballoon and the inner lumen 144 so that each of the outer lumens is influid communication with the inner lumen, as is shown in FIG. 21 and thecross-sectional view of FIG. 22.

[0150] Just distal of the balloon, near the distal seal, a distal markerband 170 is placed around the inner shaft. A flexible length of tube 172may be joined onto the distal end of the guide wire tube 166 to providea flexible tip to the catheter. The distal end 174 of the flexible tube172 is open so that a guide wire may exit the tip. Medicine orradiographic fluid may also be injected distal of the catheter throughthe guide wire lumen.

[0151] In use, the catheter 102 is inserted into the body of a patientso that the balloon is within a blood vessel. Heat exchange fluid iscirculated into the inflow port 136, travels down the inflow lumen 130and into the inner lumen 114 at the wall 162 at the end of the inflowlumen. The heat exchange fluid travels to the distal end of the innerlumen and through the slits 168 between the inner lumen 114 and theouter lumens 108, 110 and 112.

[0152] The heat exchange fluid then travels back through the three outerlumens of the balloon to the proximal end of the balloon. The outerlumens are wound in a helical pattern around the inner lumen. At somepoint along the proximal portion of the shaft, each outer lumen islocated over the portion of the shaft having a window (154, 152, 148) tothe outflow lumen and the outer balloon lumens have a plurality of slits(158, 156, 150) that are aligned with the windows. The heat transferfluid passes through the slits (158, 156, 150) through the windows (154,152, 148) and into the outflow lumen 132. From there it is circulatedout of the catheter through the outflow port 138.

[0153] Counter-current circulation between the blood and the heatexchange fluid is highly desirable for efficient heat exchange betweenthe blood and the heat exchange fluid. Thus if the balloon is positionedin a vessel where the blood flow is in the direction from the proximaltoward the distal end of the catheter, for example if it were placedfrom an insertion point in the femoral vein into the ascending venacava, it is desirable to have the heat exchange fluid in the outerballoon lumens flowing in the direction from the distal end toward theproximal end of the catheter, as is the arrangement describe above. Itis to be readily appreciated, however, that if the balloon were placedso that the blood was flowing along the catheter in the direction fromdistal to proximal, for example if the catheter was placed into theascending vena cava from an insertion point in the jugular vein, itwould be desirable to have the heat exchange fluid circulate in theouter balloon lumens from the proximal end to the distal end. This couldbe accomplished by merely reversing which port is used for inflowdirection and which for outflow.

[0154] In use, a physician may employ the method of the invention toplace a patient in a hypothermic state. By use of the Seldginertechnique, the physician may insert a heat exchange catheter having aheat exchange balloon into the femoral vein of the patient. The catheteris advanced until the heat exchange balloon is located in the inferiorvena cava. The physician then utilizes the heat exchange system tocirculate cold saline through the heat exchange balloon, which removesheat from the blood flowing past the heat exchange balloon. Thephysician continues to utilize the heat exchange system for a sufficientlength of time to reduce the temperature of the patient.

[0155] Simultaneously the physician administers an α2-adrenoreceptoragonist, non-opiod analgesic monoamine uptake inhibitor or neuropeptidein the manner and at the dosage/duration as described above. Thephysician may administer a bolus amount of the anti-shivering agent andsubsequent maintenance amounts of the agent, or may administer the agentin any other effective manner. In any event, when the patient'stemperature falls below the shivering threshold, the level ofanti-shivering agent in the patient will be sufficient to reduceshivering. This in turn makes the reduction in temperature by the heatexchange system more effective, and reduces the discomfort and otheradverse effects of shivering.

[0156] When the patient has reached the target temperature below theshivering threshold, the level of anti-shivering agent is maintained atan effective level, so that the heat exchange system can maintain thepatient precisely at the target temperature. The system has one or morepatient temperature monitors that provide feedback to the control unitfor the system. Since the amount of metabolic heat generated by the bodyis reduced, and since the thermoregulatory mechanisms of the body arenot actively opposing the temperature control of the heat exchangesystem by shivering, the target temperature can more safely and moreprecisely maintain the patient at the target temperature.

[0157] When the physician wishes to re-warm a patient slowly from ahypothermic condition below the shivering threshold, he or she mayemploy the method of the invention to more precisely control the rate ofwarming. When the patient has an effective level of anti-shivering agentso as to reduce shivering, the physician may activate the heat exchangesystem to begin in vivo core warming. The feedback from the patienttemperature monitors allows control of the heat exchange system toslowly warm the patient, or to slightly cool the blood of the patient ifthe patient's own body is functioning to warm the patient too fast.Because the very effective shivering mechanism is reduced or eliminated,the heat exchange system has sufficient power and precision to maintainthe gentle rate of warming and prevent the body from re-warming toofast.

[0158] In each of the above examples, the anti-shivering agent can beadministered before the heat exchange begins, or may be administeredonly upon the initiation of shivering, or any appropriate manner.

[0159] Each of the patents, publications, and other published documentsmentioned or referred to in this specification is herein incorporated byreference in its entirety.

[0160] While the present invention has been described with reference tothe specific embodiments thereof, it should be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted without departing from the scope of the invention. Inaddition, many modifications may be made to adapt a particularsituation, material, composition of matter, process, process step orsteps, while remaining within the scope of the present invention.Accordingly, the scope of the invention should therefore be determinedwith reference to the appended claims, along with the full range ofequivalents to which those claims are entitled.

What is claimed is:
 1. A method for reducing the temperature of all or aportion of the body of a mammalian patient to a temperature at which thepatient would exhibit a shivering response, said method comprising thesteps of: (a) sensing the temperature of all or a portion of thepatient's body; (b) generating a signal based upon said sensedtemperature; (c) controlling the temperature of all or a portion of thepatient's body based upon said signal; and (d) administering atherapeutically effective amount of a pharmaceutically acceptablepreparation of an agent selected from the group consisting of;α2-adrenoreceptor agonists, non-opiod analgesic monoamine uptakeinhibitors, neuropeptides, nefopam, and anticonvulsant agents. 2A. Amethod as in claim 1 further comprising the step of (e) placing awarming blanket on the surface of said patient.
 2. A method according toclaim 1 wherein the agent administered in Step D comprises anα2-adrenoreceptor agonist selected from the group consisting ofdexmedetomidine; detomidine; medetomidine; clonidine; bromonidine;tizanidine; mivazerol; guanfacine; oxymetazonline;(R)-(-)-3′-(2-amino-1-hydroxyethyl)-4′-fluoro-methanesulfoanilide;2-[(5-methylbenz-1-ox-4-azin-6-yl)imino]imidazoline;5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine;5,6,7,8-tetrahydro-6-(2-propenyl)-4H-thiazolo[4,5-d]azepin-2-amine;6-ethyl-5,6,7,8-tetrahydro-4H-oxaazolo[4,5-d]azepin-2-amine;5,6-dihydroxyl-1,2,3,4-tetrahydro-1-naphyl-imidazoline; andpharmaceutically acceptable salts thereof.
 3. A method according toclaim 2 wherein the α2-adrenoreceptor agonist is selected from the groupconsisting of dexmedetomidine and pharmaceutically acceptable salts ofdexmedetomidine.
 4. A method according to claim 1 wherein the agentadministered in Step D comprises a a non-opiod analgesic monoamineuptake inhibitor selected from the group consisting of nefopam;tramadol; and pharmaceutically acceptable salts thereof.
 5. A methodaccording to claim 4 wherein the non-opiod analgesic monoamine uptakeinhibitor is selected from the group consisting of nefopam and apharmaceutically acceptable salts of nefopam.
 6. A method according toclaim 1 wherein the agent administered in Step D comprises aneuropeptide selected from the group consisting of neurotensin;neurotensin analogs; bombesin; neuromedin; dermorphin; D-ala-deltorphin;and pharmaceutically acceptable variants thereof.
 7. A method accordingto claim 6 wherein the neuropeptide is selected from the groupconsisting of neurotensin and pharmaceutically acceptable variants ofneurotensin.
 8. A method according to claim 1 wherein the agentadministered in Step D comprises an anticonvulsant agent.
 9. A methodaccording to claim 8 wherein the anticonvulsant agent is selected fromthe group consisting of: hydantoins; anticonvulsant barbiturates;deoxybarbiturates; iminostilbenes; succinimides; oxazolidinediones;benzodiazepines; acetylureas; sulfonamides; carbonic anhydraseinhibitors; gabapetin; lamotrigine; primidone; valproate; pro-drugs ormetabolic precursors of any such antoconvulsant agents; and, possiblecombinations thereof.
 10. A method according to claim 9 wherein thehydantoins comprise phenytoin.
 11. A method according to claim 9 whereinthe anticonvulsant barbiturates compromise Phenobarbital.
 12. A methodaccording to claim 9 wherein the deoxybarbiturates comprise primidone.13. A method according to claim 9 wherein the iminostilbenes comprisecarbamazepine.
 14. A method according to claim 9 wherein thesuccinimides comprise ethosuximide, methsuximide and phensuximide.
 15. Amethod according to claim 9 wherein the oxazolidinediones comprisetrimethadione and paramethadione.
 16. A method according to claim 9wherein the benzodiazepines comprise diazepam, chlordiazeppoxide,oxazepam, chlorazepate, nitrazepam, clonazepam and lorazepam.
 17. Amethod according to claim 9 wherein the acetylureas comprise phenacemideand pheneturide.
 18. A method according to claim 9 wherein thesulfonamides and carbonic anhydrase inhibitors comprise acetazolamide,sulthiame and bromide.
 19. A method according to claim 9 wherein theanticonvulsant agent comprises a metabolic precursor of phentoin.
 20. Amethod according to claim 19 wherein the metabolic precursor of phentoincomprises fosphenytoin. 21 A method according to claim 20 whereinfosphenytoin is aministered in two doses, 15 minutes apart.
 22. A methodaccording to claim 21 wherein each dose contains approximately 20 mgoffosphenytoin per kg of body weight.
 23. A method according to claim 20wherein fosphenytoin is administered intravenously at an approximaterate of 150 mgper minute.
 24. A method according to claim 1 wherein thetemperature controlling step (c) includes lowering the temperature belowthe set point temperature.
 25. A method according to claim 1 wherein thetemperature controlling step (c) includes raising the temperature froman initial temperature below the set point temperature.
 26. A methodaccording to claim 9 wherein the temperature controlling step (c)includes raising the temperature at a predetermined rate.
 27. A methodaccording to claim 9 wherein the temperature controlling step (c)includes maintaining the temperature at a stable temperature below theset point temperature.
 28. A method according to claim 11 wherein thestable temperature is normothermia.
 29. A method according to claim 1wherein the temperature controlling step (c) includes placing a heatexchanger into the patient's vasculature and using the heat exchanger tocool the patient's blood, thereby resulting in cooling of all or aportion of the patient's body.
 30. A method according to claim 13wherein the heat exchanger comprises a catheter that has a heat exchangeregion.
 31. A method according to claim 30 wherein the heat exchangeregion of the catheter comprises a balloon through which heat exchangefluid is circulated.